DESCRIPTION (From the Applicant's Abstract): Three visual pigments mediate trichromatic color vision in humans, Old World monkeys and apes. Genes that are nearly identical encode the middle- and long-wavelength sensitive pigments, abbreviated M and L, respectively. The M and L genes lie in a head-to-tail tandem array on the X-chromosome and were produced by a gene duplication event that is estimated to have occurred in the primate lineage about 35-60 million years ago. The short-wavelength sensitive pigment (S) is encoded by an autosome, and is estimated to have diverged from the ancestral M/L gene about 800-1 100 million years ago. The vast majority of cones in human and primate retina are either M or L cones, with only about 7 percent of cones being S. Among the L and M cones, each cell exclusively expresses only one pigment gene from the X-chromosome array. There are two fundamentally important unsolved mysteries regarding expression of the X-linked visual pigment genes that are the focus of this grant. First, do the M and L cones represent two distinct cell types, so that an M cone specific mechanism directs expression of M pigment, and an L cone specific mechanism directs expression of L pigment? In this scenario, the M and L cones are uniquely different, and the fact that they express different pigments is secondary to these other differences. Or, are the M and L cones one cell type in which there is a stochastic process that directs mutually exclusive expression of one of the X-chromosome pigment genes? In this scenario, the identity of the gene chosen for expression determines whether the cone will be an M or an L cone. The second mystery is, what determines which of the genes from an individual array are expressed? Recent evidence suggests that in arrays with 3 genes, the last gene in the array (3' most) is not expressed. But what about arrays with 4 genes, is the third gene expressed? Solving these two mysteries will have profound impact on our understanding of the fundamental biological processes that determine the organization of the photoreceptor mosaic, and of how neural circuits are wired to extract color information at the first synapse. Towards solving these mysteries we propose the following 4 specific aims: 1) To characterize the expression pattern of downstream genes, 2) To test the model for the mechanism that produces the high degree of L and M gene sequence polymorphism in humans implied from the observed expression pattern of downstream genes, 3) To conduct developmental and comparative studies to test the stochastic model; 4) To develop innovative models for directly testing the stochastic model.